JP2020514684A - 質量分析によってbraf突然変異および野生型brafタンパク質を定める方法 - Google Patents
質量分析によってbraf突然変異および野生型brafタンパク質を定める方法 Download PDFInfo
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Abstract
Description
SEQ ID 1: DLTVKIGDFGLATVKSRWSGSHQFE (WT),
SEQ ID 2: DLTVKIGDFGLATE (V600E),
SEQ ID 3: DLTVKIGDFGLATKKSRWSGSHQFE (V600K),
SEQ ID 4: DLTVKIGDFGLATRKSRWSGSHQFE (V600R) and
SEQ ID 5: DLTVKIGDFGLATDKSRWSGSHQFE (V600D)
SEQ ID 6: FGLATE (V600E),
SEQ ID 7: GLATD (V600D),
を、幾分長い特異的BRAF
SEQ ID 8: FGLATVKSRWSGSHQFE (WT),
SEQ ID 9: FGLATKKSRWSGSHQFE (V600K), and
SEQ ID 10: FGLATRKSRWSGSHQFE (V600R).
ペプチド配列に加えて生成することができた。
SEQ ID 11: LTVKIGDFGLATVKSRWSGSHQFE (WT)
SEQ ID 12: DFGLATVKSRWSGSHQFE (WT)
SEQ ID 13: DLTVKIGDFGLATEKSRWSGSHQFE (V600E)
SEQ ID 14: DFGLATEKSRWSGSHQFE (V600E)
SEQ ID 15: FGLATEKSRWSGSHQFE (V600E)
SEQ ID 16: LTVKIGDFGLATEKSRWSGSHQFE (V600E)
SEQ ID 17: DLTVKIGDFGLATEKSRWSGSHQFE (V600E)
SEQ ID 18: LTVKIGDFGLATEKSRWSGSHQFE (V600E)
SEQ ID 19: DFGLATEKSRWSGSHQFE (V600E)
SEQ ID 20: FGLATEKSRWSGSHQFE (V600E)
SEQ ID 21: LTVKIGDFGLATE (V600E)
SEQ ID 22: DFGLATE (V600E)
SEQ ID 23: DFGLATKKSRWSGSHQFE (V600K)
SEQ ID 24: FGLATKKSRWSGSHQFE (V600K)
SEQ ID 25: LTVKIGDFGLATKKSRWSGSHQFE (V600K)
SEQ ID 26: DLTVKIGDFGLATKSRWSGSHQFE (V600K)
SEQ ID 27: LTVKIGDFGLATKKSRWSGSHQFE (V600K)
SEQ ID 28: DFGLATKKSRWSGSHQFE (V600K)
SEQ ID 29: DFGLATRKSRWSGSHQFE (V600R)
SEQ ID 30: FGLATRKSRWSGSHQFE (V600R)
SEQ ID 31: LTVKIGDFGLATRKSRWSGSHQFE (V600R)
SEQ ID 32: DLTVKIGDFGLATRKSRWSGSHQFE (V600R)
SEQ ID 33: LTVKIGDFGLATRKSRWSGSHQFE (V600R)
SEQ ID 34: DFGLATRKSRWSGSHQFE (V600R)
SEQ ID 35: DFGLATDKSRWSGSHQFE (V600D)
SEQ ID 36: FGLATDKSRWSGSHQFE (V600D)
SEQ ID 37: LTVKIGDFGLATDKSRWSGSHQFE (V600D)
SEQ ID 38: DLTVKIGDFGLATDKSRWSGSHQFE (V600D)
SEQ ID 39: LTVKIGDFGLATDKSRWSGSHQFE (V600D)
SEQ ID 40: DFGLATDKSRWSGSHQFE (V600D)
SEQ ID 41: FGLATDKSRWSGSHQFE (V600D)
SEQ ID 42: DLTVKIGDFGLATD (V600D)
SEQ ID 43: LTVKIGDFGLATD (V600D)
SEQ ID 44: DFGLATD (V600D)
SEQ ID 45: FGLATD (V600D)
以下の実施例はさらなる実施例であり、決して本発明の範囲を限定するものと解釈されるべきではない。本発明は添付の請求項のみによって限定される。
−20Cにて実行するクリオスタットを用いて、腫瘍からの凍結組織サンプルを10×10μmの厚さの切片にスライスした。200μlの50mM重炭酸アンモニウムおよび6M尿素の中で切片を溶解した。ホルマリン固定パラフィン包埋腫瘍組織を、ミクロトームを用いて切片にするか、またはパラフィン包埋ブロックからコアを切り取った。En Vision TM FLEX target retrival solution(高pH)(Dako、Glostrup、デンマーク(Denmark)を用いて、切片またはコアを脱パラフィンし、98Cにて10分間加熱した。サンプルを、4Cにて14000×gで10分間遠心分離した。表面に浮遊するパラフィンを除去し、回収溶液(retrieval solution)を吸引した。このステップを1回繰り返した。このサンプルに、300μLの50mM重炭酸アンモニウム中の6M塩化グアニジンを加えた。サンプルをBranson Sonifier250(出力4、10%デューティサイクル)で2分間超音波処理した後、10000gにて5分間遠心分離した。
Read Glead Discovery AB(Lund,Sweden)によって、95%より高純度のペプチドの供給を受けた。
Skyline v3.1.0ソフトウェア(MacCoss Lab Software、Seattle、WA)にて遷移リストを作成した。最初に、2+、3+、および4+荷電状態における各ペプチドに対して、多い数の遷移、基準に適合するすべての可能なyイオンシリーズ(m/z>前駆物質−2から最終イオン−2、前駆物質m/z排除ウィンドウ:20Th)を選択した。
TSQ Vantageトリプル四重極質量分析計(Thermo Scientific、Waltham、MA)を用いたナノLC−MS/MSによって、ペプチド混合物を分析した。TSQは、Easy n−LCIIポンプ(Thermo Scientific、Waltham、MA)を備えていた。サンプルを、プレカラムAcclaim PepMap100C8(5×0.3mm、5μm)(Thermo Scientific、Waltham、MA)に注入し、オンライン脱塩および濃縮の後に、Acclaim PepMap100C8(150μm×0.075mm、3μm)(Thermo Scientific、Waltham、MA)においてペプチドを分離した。0.1%ギ酸を含有する10〜35%アセトニトリルからの35min直線勾配において分離を行った。流速は300nL/minであった。MS分析は正イオンモードで行い、スプレー電圧およびデクラスタリング電位はそれぞれ1750Vおよび0に設定した。トランスファーキャピラリ温度を270℃に設定し、Sレンズの振幅は143であった。単位分解能(0.7FWHM)にて動作するQ1およびQ3においてSRM遷移を取得し、Q2における衝突ガス圧力を1.2mTorrに設定した。サイクル時間は3.0sであった。Skylineのデータのマニュアル検査によって前駆物質当りの遷移を選択し、最終アッセイに対してスケジュールした遷移リストを作成した。ヒトMM組織消化物にペプチド混合物を加えることによって、選択した遷移を実際のマトリックスにおいてテストした。
QExactive質量分析計(Thermo Scientific、Waltham、MA)を用いたナノLC−MS/MSによって、ペプチド混合物を分析した。QExactiveは、Easy n−LC1000ポンプ(Thermo Scientific、Waltham、MA)を備えていた。サンプルをプレカラムAcclaim PepMap100C8(5×0.3mm、5μm)(Thermo Scientific、Waltham、MA)に注入し、オンライン脱塩および濃縮の後に、Acclaim PepMap100C8(150μm×0.075mm、3μm)(Thermo Scientific、Waltham、MA)においてペプチドを分離した。0.1%ギ酸を含有する5〜40%アセトニトリルからの60min直線勾配において分離を行った。流速は300nL/minであった。Orbitrap質量分析計において、m/z400〜1600の範囲で分解能70,000(m/z200)によって全MS走査を取得した。標的値は1.00E+06であった。この方法はBRAFペプチドに対する包含リストを含んでおり、荷電状態2以上を有する15の最も強いピークを30%の標準化衝突エネルギを有するHCD衝突セルにおいてフラグメント化し、m/z200における分解能17,500を有するOrbitrap質量分析計においてタンデム質量スペクトルを取得した。標的値は1.00E+05であった。イオン選択閾値は3.30E+05カウントであり、最大許容イオン蓄積時間は全MS走査に対して100msであり、タンデム質量スペクトルに対して60msであった。Skylineのデータのマニュアル検査によって前駆物質当りの遷移を選択し、最終アッセイに対してスケジュールした遷移リストを作成した。ヒトMM組織消化物にペプチド混合物を加えることによって、選択した遷移を実際のマトリックスにおいてテストした。
よってV600WT、V600E、V600D、V600R、およびV600Kに対する10の一意のペプチドフラグメントを見出し、その一部を図2に示しており、ここには新鮮凍結腫瘍サンプルからの腫瘍組織可溶化物における、BRAFの野生型および4つの突然変異体のGluC生成ペプチドに対するSRMシグネチャー前駆物質クロマトグラフィーピークを示す。ペプチドに対する対応するSRMシグネチャーを得て、これを図3においてA)野生型およびB)V600Eについて示している。表1は、これらのペプチド(配列番号1から配列番号5)のSRM/MRMシグネチャークロマトグラフィーピークに対する特徴をさらにまとめたものである。
SEQ ID NO: 1: DLTVKIGDFGLATVKSRWSGSHQFE
モノアイソトピック質量:2779.10
前駆物質m/z:1389.714(荷電状態:2)
遷移m/z:1548.7554 (y13), 1447.7077 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1332.2006 (y24), 1275.6586 (y23), 1225.1348 (y22), 1175.6006 (y21), 1111.5531 (y20), 1055.0111 (y19), 1026.5003 (y18), 968.9868 (y17), 895.4526 (y16), 866.9419 (y15), 810.3999 (y14), 774.8813 (y13), 724.3575 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5)。
遷移m/z:1548.7554 (y13), 1447.7077 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1332.2006 (y24), 1275.6586 (y23), 1225.1348 (y22), 1175.6006 (y21), 1111.5531 (y20), 1055.0111 (y19), 1026.5003 (y18), 968.9868 (y17), 895.4526 (y16), 866.9419 (y15), 810.3999 (y14), 774.8813 (y13), 724.3575 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 888.4695 (y24), 850.7748 (y23), 817.0923 (y22), 784.0695 (y21), 741.3711 (y20), 703.6765 (y19), 684.6693 (y18), 646.3270 (y17), 597.3042 (y16), 578.2970 (y15), 540.6023 (y14), 516.9233 (y13), 483.2407 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
遷移m/z:1548.7554 (y13), 1447.7077 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1332.2006 (y24), 1275.6586 (y23), 1225.1348 (y22), 1175.6006 (y21), 1111.5531 (y20), 1055.0111 (y19), 1026.5003 (y18), 968.9868 (y17), 895.4526 (y16), 866.9419 (y15), 810.3999 (y14), 774.8813 (y13), 724.3575 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 888.4695 (y24), 850.7748 (y23), 817.0923 (y22), 784.0695 (y21), 741.3711 (y20), 703.6765 (y19), 684.6693 (y18), 646.3270 (y17), 597.3042 (y16), 578.2970 (y15), 540.6023 (y14), 516.9233 (y13), 483.2407 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
モノアイソトピック質量:2795.06
前駆物質m/z:1397.693(荷電状態:2)
遷移m/z:1564.7139 (y13), 1463.6662 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1340.1799 (y24), 1283.6379 (y23), 1233.1140 (y22), 1183.5798 (y21), 1119.5323 (y20), 1062.9903 (y19), 1034.4796 (y18), 976.9661 (y17), 903.4319 (y16), 874.9212 (y15), 818.3791 (y14), 782.8606 (y13), 732.3367 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5)。
遷移m/z:1564.7139 (y13), 1463.6662 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1340.1799 (y24), 1283.6379 (y23), 1233.1140 (y22), 1183.5798 (y21), 1119.5323 (y20), 1062.9903 (y19), 1034.4796 (y18), 976.9661 (y17), 903.4319 (y16), 874.9212 (y15), 818.3791 (y14), 782.8606 (y13), 732.3367 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 893.7890 (y24), 856.0943 (y23), 822.4118 (y22), 789.3890 (y21), 746.6907 (y20), 708.9960 (y19), 689.9888 (y18), 651.6465 (y17), 602.6237 (y16), 583.6165 (y15), 545.9219 (y14), 522.2428 (y13), 488.5603 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
遷移m/z:1564.7139 (y13), 1463.6662 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1340.1799 (y24), 1283.6379 (y23), 1233.1140 (y22), 1183.5798 (y21), 1119.5323 (y20), 1062.9903 (y19), 1034.4796 (y18), 976.9661 (y17), 903.4319 (y16), 874.9212 (y15), 818.3791 (y14), 782.8606 (y13), 732.3367 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 893.7890 (y24), 856.0943 (y23), 822.4118 (y22), 789.3890 (y21), 746.6907 (y20), 708.9960 (y19), 689.9888 (y18), 651.6465 (y17), 602.6237 (y16), 583.6165 (y15), 545.9219 (y14), 522.2428 (y13), 488.5603 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
モノアイソトピック質量:2836.16
前駆物質m/z:1418.23(荷電状態:2)
遷移m/z:1504.7404 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1360.7170 (y24), 1304.1750 (y23), 1253.6511 (y22), 1204.1169 (y21), 1140.0694 (y20), 1083.5274 (y19), 1055.0167 (y18), 997.5032 (y17), 923.9690 (y16), 895.4583 (y15), 838.9162 (y14), 803.3977 (y13), 752.8738 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5)。
遷移m/z:1504.7404 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1360.7170 (y24), 1304.1750 (y23), 1253.6511 (y22), 1204.1169 (y21), 1140.0694 (y20), 1083.5274 (y19), 1055.0167 (y18), 997.5032 (y17), 923.9690 (y16), 895.4583 (y15), 838.9162 (y14), 803.3977 (y13), 752.8738 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 907.4804 (y24), 869.7857 (y23), 836.1032 (y22), 803.0804 (y21), 760.3820 (y20), 722.6874 (y19), 703.6802 (y18), 665.3379 (y17), 616.3151 (y16), 597.3079 (y15), 559.6132 (y14), 535.9342 (y13), 502.2516 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
遷移m/z:1504.7404 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1360.7170 (y24), 1304.1750 (y23), 1253.6511 (y22), 1204.1169 (y21), 1140.0694 (y20), 1083.5274 (y19), 1055.0167 (y18), 997.5032 (y17), 923.9690 (y16), 895.4583 (y15), 838.9162 (y14), 803.3977 (y13), 752.8738 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 907.4804 (y24), 869.7857 (y23), 836.1032 (y22), 803.0804 (y21), 760.3820 (y20), 722.6874 (y19), 703.6802 (y18), 665.3379 (y17), 616.3151 (y16), 597.3079 (y15), 559.6132 (y14), 535.9342 (y13), 502.2516 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
モノアイソトピック質量:2808.15
前駆物質m/z:1404.227(荷電状態:2)
遷移m/z:1577.7819 (y13), 1476.7342 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1346.7139 (y24), 1290.1719 (y23), 1239.6480 (y22), 1190.1138 (y21), 1126.0664 (y20), 1069.5243 (y19), 1041.0136 (y18), 983.5001 (y17), 909.9659 (y16), 881.4552 (y15), 824.9132 (y14), 789.3946 (y13), 738.8708 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5)。
遷移m/z:1577.7819 (y13), 1476.7342 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1346.7139 (y24), 1290.1719 (y23), 1239.6480 (y22), 1190.1138 (y21), 1126.0664 (y20), 1069.5243 (y19), 1041.0136 (y18), 983.5001 (y17), 909.9659 (y16), 881.4552 (y15), 824.9132 (y14), 789.3946 (y13), 738.8708 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 898.1450 (y24), 860.4504 (y23), 826.7678 (y22), 793.7450 (y21), 751.0467 (y20), 713.3520 (y19), 694.3448 (y18), 656.0025 (y17), 606.9797 (y16), 587.9725 (y15), 550.2779 (y14), 526.5988 (y13), 492.9163 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
遷移m/z:1577.7819 (y13), 1476.7342 (y12), 1348.6393 (y11), 1220.5443 (y10), 1133.5123 (y9), 977.4112 (y8), 791.3319 (y7), 704.2998 (y6), 647.2784 (y5), 560.2463 (y4), 423.1874 (y3), 1346.7139 (y24), 1290.1719 (y23), 1239.6480 (y22), 1190.1138 (y21), 1126.0664 (y20), 1069.5243 (y19), 1041.0136 (y18), 983.5001 (y17), 909.9659 (y16), 881.4552 (y15), 824.9132 (y14), 789.3946 (y13), 738.8708 (y12), 674.8233 (y11), 610.7758 (y10), 567.2598 (y9), 489.2092 (y8), 396.1696 (y7), 352.6536 (y6), 324.1428 (y5), 898.1450 (y24), 860.4504 (y23), 826.7678 (y22), 793.7450 (y21), 751.0467 (y20), 713.3520 (y19), 694.3448 (y18), 656.0025 (y17), 606.9797 (y16), 587.9725 (y15), 550.2779 (y14), 526.5988 (y13), 492.9163 (y12), 450.2179 (y11), 407.5196 (y10), 378.5089 (y9), 326.4752 (y8)。
モノアイソトピック質量:1478.66
前駆物質m/z:739.8905(荷電状態:2)
遷移m/z:1363.7468 (y13), 1250.6627 (y12), 1149.6150 (y11), 1050.5466 (y10), 922.4516 (y9), 809.3676 (y8), 752.3461 (y7), 637.3192 (y6), 490.2508 (y5), 433.2293 (y4), 320.1452 (y3), 682.3770 (y13), 625.8350 (y12), 575.3111 (y11), 525.7769 (y10), 461.7295 (y9), 405.1874 (y8), 376.6767 (y7), 319.1632 (y6)。
遷移m/z:1363.7468 (y13), 1250.6627 (y12), 1149.6150 (y11), 1050.5466 (y10), 922.4516 (y9), 809.3676 (y8), 752.3461 (y7), 637.3192 (y6), 490.2508 (y5), 433.2293 (y4), 320.1452 (y3), 682.3770 (y13), 625.8350 (y12), 575.3111 (y11), 525.7769 (y10), 461.7295 (y9), 405.1874 (y8), 376.6767 (y7), 319.1632 (y6), 455.2538 (y13), 417.5591 (y12), 383.8765 (y11), 350.8537 (y10), 308.1554 (y9)。
遷移m/z:1363.7468 (y13), 1250.6627 (y12), 1149.6150 (y11), 1050.5466 (y10), 922.4516 (y9), 809.3676 (y8), 752.3461 (y7), 637.3192 (y6), 490.2508 (y5), 433.2293 (y4), 320.1452 (y3), 682.3770 (y13), 625.8350 (y12), 575.3111 (y11), 525.7769 (y10), 461.7295 (y9), 405.1874 (y8), 376.6767 (y7), 319.1632 (y6), 455.2538 (y13), 417.5591 (y12), 383.8765 (y11), 350.8537 (y10), 308.1554 (y9)。
Claims (15)
- 生物学的サンプル中の野生型(WT)BRAFタンパク質とそのタンパク質変異体とのモル比を定めるための方法であって、
a)グルタミン酸残基に対するC末端のペプチド結合、またはグルタミン酸もしくはアスパラギン酸残基に対するC末端のペプチド結合を特異的に切断するセリンプロテイナーゼを用いることによって前記サンプルを消化して、前記プロテイナーゼによる前記ペプチドの消化によってもたらされたペプチドフラグメントを含む組成物を得るステップであって、前記フラグメントの質量は前記野生型(WT)B−rafタンパク質とBRAFタンパク質変異体とで異なる、ステップと、
b)質量分析技術を用いて、野生型(WT)B−rafタンパク質の消化からもたらされたペプチドフラグメントのモル量と、前記野生型(WT)B−rafタンパク質の変異体の消化からもたらされたペプチドフラグメントのモル量とを定量的にアッセイするステップと、
c)前記定量的評価に基づいて、前記WT BRAFタンパク質とその変異体との少なくとも1つの特異的比率を算出するステップとを含む、前記方法。 - 前記BRAFタンパク質変異体は、WT BRAFのアミノ酸位置600に対応する位置において突然変異した変異体であり、前記WT BRAFにおいて前記位置はバリンによって占められている、請求項1に記載の方法。
- 前記BRAFタンパク質変異体はBRAF V600E、V600D、V600R、および/またはV600Kである、請求項2に記載の方法。
- 前記セリンプロテイナーゼはグルタミルエンドペプチダーゼ(Glu−C)である、請求項1〜3のいずれか一項に記載の方法。
- 前記消化ステップは、前記サンプルを酢酸アンモニウム、重炭酸アンモニウム、および/またはリン酸緩衝剤で処理するステップを含む、請求項1〜4のいずれか一項に記載の方法。
- 前記サンプルは腫瘍組織サンプルまたは体液である、請求項1〜5のいずれか一項に記載の方法。
- 前記サンプルは腫瘍組織であり、前記腫瘍組織は悪性メラノーマ、甲状腺癌、結腸直腸癌、肺癌、脳腫瘍癌、低悪性度神経膠腫、または卵巣癌腫瘍からの組織である、請求項1〜6のいずれか一項に記載の方法。
- 前記定量的評価ステップにおいて用いられる野生型(WT)B−rafタンパク質の消化によってもたらされるポリペプチドフラグメントは、配列番号1および/または配列番号8によるポリペプチドである、請求項1〜7のいずれか一項に記載の方法。
- 前記定量的評価ステップにおいて測定される前記野生型(WT)B−rafタンパク質のタンパク質変異体の消化によってもたらされるポリペプチドフラグメントは、配列番号2、配列番号3、配列番号4、配列番号5、配列番号6、配列番号7、配列番号9、および/または配列番号10によるポリペプチドである、請求項3に記載の方法。
- 前記質量分析技術は、質量分析技術に整合する液体クロマトグラフィーである、請求項1〜7のいずれか一項に記載の方法。
- 質量分析技術に整合する前記質量液体クロマトグラフィーはHPLC/ESI−MSである、請求項8に記載の方法。
- BRAF関連疾患のための所与の薬物処置に対する対象の感受性を推定するための方法であって、
(i)BRAF関連疾患である対象からのサンプルを提供し、請求項1〜9のいずれか一項に記載の方法によってWT BRAFタンパク質とその変異体との特異的モル比を定めるステップ、
(ii)前記BRAF関連疾患であり、かつ前記所与の薬物処置に感受性であることが既知である対象からの多数のサンプルから定められたWT BRAFタンパク質とその変異体との特異的モル比の基準値と、WT BRAFタンパク質とその変異体とのモル特異的比とを比較するステップ、
(iii)前記比較に基づいて、所与の薬物処置に対する前記対象の感受性を定めるステップを含み、
前記サンプル中の前記少なくとも1つのBRAFタンパク質変異体に対するWT BRAFの比率が、前記少なくとも1つのBRAFタンパク質変異体に対するWT BRAFの前記比率の基準値よりも高いことで、所与の薬物処置に対する感受性の増加が示される、前記方法。 - 前記薬物処置は、たとえばベムラフェニブ、ダブラフェニブ、またはソラフェニブなどのキナーゼ阻害剤を用いた処置である、請求項12に記載の方法。
- 所与の薬物処置に対する対象の感受性が処置前および処置後にモニタされ、WT BRAFタンパク質とその変異体との特異的モル比の動作前および動作後の変化は腫瘍組織の突然変異状態の変化を示す、請求項12または13に記載の方法。
- BRAF関連疾患を有する対象に対する処置の方法であって、以下を提供するステップ、
(i)BRAF関連疾患である対象からのサンプルを提供し、請求項1〜9のいずれか一項に記載の方法によってWT BRAFタンパク質とその変異体との特異的モル比を定めるステップと、
(ii)前記BRAF関連疾患であり、かつ前記所与の薬物処置に感受性であることが既知である対象からの多数のサンプルから定められたWT BRAFタンパク質とその変異体との特異的モル比の基準値と、WT BRAFタンパク質とその変異体とのモル特異的比とを比較するステップと、
(iii)前記比較に基づいて、所与の薬物処置に対する前記対象の感受性を定めるステップであって、前記サンプル中の前記少なくとも1つのBRAFタンパク質変異体に対するWT BRAFの比率が、前記少なくとも1つのBRAFタンパク質変異体に対するWT BRAFの前記比率の基準値よりも高いことで、所与の薬物処置に対する感受性の増加が示される、ステップと、
(iv)もし患者が所与の薬物処置に対して感受性であることが見出されれば、処方されたかもしくは規定された1日用量(DDD)の前記薬物処置の前記薬物を処方された処置期間投与するか、あるいは
もし前記患者が所与の薬物処置に対して感受性でないことが見出されれば、代わりにたとえば手術、放射線療法、化学療法、免疫療法、および/または前記BRAF関連疾患に対して有益なその他の処置などの代替処置を開始するステップとを含む、前記方法。
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008220299A (ja) * | 2007-03-14 | 2008-09-25 | Sysmex Corp | 癌の診断支援装置 |
JP2012237586A (ja) * | 2011-05-10 | 2012-12-06 | Fujirebio Inc | 抗がん剤の効果的な治療方法を選択するための診断試薬 |
US20140051105A1 (en) * | 2011-01-17 | 2014-02-20 | The Johns Hopkins University | Mutant Proteins as Cancer-Specific Biomarkers |
JP2014532184A (ja) * | 2011-10-12 | 2014-12-04 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒルThe University Of North Carolina At Chapel Hill | 多重化キナーゼ阻害剤ビーズ及びその使用 |
WO2015145151A1 (en) * | 2014-03-25 | 2015-10-01 | Pelago Bioscience AB | Method for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
WO2016007959A1 (en) * | 2014-07-11 | 2016-01-14 | Expression Pathology, Inc. | Srm/mrm assay for the serine/threonine-protein kinase b-raf (braf) |
WO2016104794A1 (ja) * | 2014-12-26 | 2016-06-30 | 国立研究開発法人国立がん研究センター | Braf変異検出によるegfr阻害剤の効果予測 |
JP2016528879A (ja) * | 2013-06-17 | 2016-09-23 | アルモ・バイオサイエンシーズ・インコーポレイテッド | タンパク質の同一性および安定性を評価する方法 |
JP2016535270A (ja) * | 2013-08-13 | 2016-11-10 | エレクトロフォレティクス リミテッド | 膵臓癌に関連する物質及び方法 |
JP2016204365A (ja) * | 2015-04-16 | 2016-12-08 | 日東電工株式会社 | Braf遺伝子変異を有する細胞に対する細胞死誘導剤、当該細胞の増殖抑制剤及び当該細胞の増殖異常に起因する疾患の治療用医薬組成物 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2003286447A1 (en) * | 2003-10-16 | 2004-06-06 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Treatments for inhibiting development and progression of nevi and melanoma having braf mutations |
US10634669B2 (en) * | 2011-12-06 | 2020-04-28 | Chunli Liu | Methods and antibodies for designing and detecting mutation-specific or hidden epitope/antigena |
WO2013155077A1 (en) * | 2012-04-09 | 2013-10-17 | Board Of Regents,The University Of Texas System | Response markers for src inhibitor therapies |
WO2015187512A1 (en) * | 2014-06-01 | 2015-12-10 | Trovagene, Inc. | Monitoring treatment of histiocytosis with vemurafenib and dabrafenib |
-
2017
- 2017-12-19 KR KR1020197020968A patent/KR20190111932A/ko not_active Application Discontinuation
- 2017-12-19 HU HUE17838039A patent/HUE055970T2/hu unknown
- 2017-12-19 WO PCT/EP2017/083547 patent/WO2018114953A1/en unknown
- 2017-12-19 CN CN201780078506.6A patent/CN110291403B/zh active Active
- 2017-12-19 DK DK17838039.0T patent/DK3559674T3/da active
- 2017-12-19 BR BR112019012441A patent/BR112019012441A2/pt unknown
- 2017-12-19 ES ES17838039T patent/ES2891530T3/es active Active
- 2017-12-19 US US16/470,551 patent/US20190339286A1/en not_active Abandoned
- 2017-12-19 EP EP17838039.0A patent/EP3559674B1/en active Active
- 2017-12-19 JP JP2019529249A patent/JP2020514684A/ja active Pending
-
2019
- 2019-06-13 IL IL267325A patent/IL267325A/en unknown
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2008220299A (ja) * | 2007-03-14 | 2008-09-25 | Sysmex Corp | 癌の診断支援装置 |
US20140051105A1 (en) * | 2011-01-17 | 2014-02-20 | The Johns Hopkins University | Mutant Proteins as Cancer-Specific Biomarkers |
JP2012237586A (ja) * | 2011-05-10 | 2012-12-06 | Fujirebio Inc | 抗がん剤の効果的な治療方法を選択するための診断試薬 |
JP2014532184A (ja) * | 2011-10-12 | 2014-12-04 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒルThe University Of North Carolina At Chapel Hill | 多重化キナーゼ阻害剤ビーズ及びその使用 |
JP2016528879A (ja) * | 2013-06-17 | 2016-09-23 | アルモ・バイオサイエンシーズ・インコーポレイテッド | タンパク質の同一性および安定性を評価する方法 |
JP2016535270A (ja) * | 2013-08-13 | 2016-11-10 | エレクトロフォレティクス リミテッド | 膵臓癌に関連する物質及び方法 |
WO2015145151A1 (en) * | 2014-03-25 | 2015-10-01 | Pelago Bioscience AB | Method for identifying a biomarker indicative of a reduced drug response using a thermal shift assay |
WO2016007959A1 (en) * | 2014-07-11 | 2016-01-14 | Expression Pathology, Inc. | Srm/mrm assay for the serine/threonine-protein kinase b-raf (braf) |
WO2016104794A1 (ja) * | 2014-12-26 | 2016-06-30 | 国立研究開発法人国立がん研究センター | Braf変異検出によるegfr阻害剤の効果予測 |
JP2016204365A (ja) * | 2015-04-16 | 2016-12-08 | 日東電工株式会社 | Braf遺伝子変異を有する細胞に対する細胞死誘導剤、当該細胞の増殖抑制剤及び当該細胞の増殖異常に起因する疾患の治療用医薬組成物 |
Non-Patent Citations (4)
Title |
---|
CHEN, H. ET AL.: "Quantitative analysis of wild-type and V600E mutant BRAF proteins in colorectal carcinoma using immu", ANALYTICA CHIMICA ACTA, vol. 933, JPN5020002154, 2 June 2016 (2016-06-02), NL, pages 144 - 155, XP029672879, ISSN: 0004958813, DOI: 10.1016/j.aca.2016.05.037 * |
OKIMOTO, ROSS A., ET AL.: "Preclinical efficacy of a RAF inhibitor that evades paradoxical MAPK pathway activation in protein k", PROC. NATL. ACAD. SCI. U. S. A., vol. 113, JPN6022036143, 22 November 2016 (2016-11-22), pages 13456 - 13461, XP055544950, ISSN: 0004861766, DOI: 10.1073/pnas.1610456113 * |
TSIATSIANI, L. AND HECK, A. J. R.: "Proteomics beyond trypsin", THE FEBS JOURNAL, vol. 282, JPN6021040698, 30 March 2015 (2015-03-30), pages 2612 - 2626, ISSN: 0004958812 * |
WALLENTINE, J. C. ET AL.: "Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed-Sternberg cells by LC-MS/M", LABORATORY INVESTIGATION, vol. 87, JPN6021040699, 17 September 2007 (2007-09-17), pages 1113 - 1124, XP055429169, ISSN: 0004958814, DOI: 10.1038/labinvest.3700672 * |
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EP3559674A1 (en) | 2019-10-30 |
IL267325A (en) | 2019-08-29 |
ES2891530T3 (es) | 2022-01-28 |
BR112019012441A2 (pt) | 2020-04-14 |
US20190339286A1 (en) | 2019-11-07 |
CN110291403B (zh) | 2022-09-16 |
EP3559674B1 (en) | 2021-07-07 |
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